16alpha-bromo-and 16alpha-iodo pregnanes



United States Patent ()fitice Patented June 15,1955

3,189,626 lm-BROMO- AND lu-IQDQ PREGNANES Donald E. Ayer, Portage Township, Kalamazoo County, Mich, assignor to The Upjohn Company, Kalamazoo, Mich, a corporation of Delaware No Drawing. Filed Dec. 11, 1963, Ser; No. 329,894 3 Claims. (Cl. 2fi0-.37.45),

This invention relates to novel steroid compounds and is more particularly concerned with anti-inflammatory lfiwbromoand 16ai0d0- l 1 8, l7a-dihydroxypregnenes and intermediates in the production thereof.

It is an obiect of the present invention to provide new anti-inflammatory steroids having a 16oc-b10n10 or 16aiodo group in their structure. It is a further object of this invention to provide an elegant method to produce these plication. The compounds can also be applied in the case.

of ketosis of cattle.

The compounds are further useful for the production of other steroids since they havethe advantage of not forming 16,17-oxido compounds by elimination of hydro-- gen halide when in contact with a basic medium. The.

corresponding l6B-halo compounds will readily undergo precisely such an elimination reaction and are therefore not useful in many chemical syntheses. The 16a-halo group may be used to introduce other substituents in this position, e.g. by metathetic reactions to give other halo substituted steroids, alkyl substituted or hydroxy substituted steroids and the like.

The anti-inflammatory activity of 6u-methyl=9a-fluoro- 1 6cc-bIOII10-l 1B, 17a-dihydroxy 1,4-pregnadiene-3,20-dione was found to be 44 times that of hydrocortisone in the granuloma pouch. Since the same compound had a thymus involution activity of only 10 times that of hydrocortisone, favorable pharmaceutical ratios are indicated.

The processes to produce the compounds of this application and the starting materials necessary to produce such compounds are shown in the examples.

Example I .-1 6a-br0m0-6 a-methyZ-Qa-flimm-I 1 5,1 7a-dihydroxy-l ,4-pregnadiene-3,2g9-dione A solution was prepared containing 500 mg. of 6amethyl9m-fiuoro-l lB-hydroxy 1,4,16-pregnatrine-3 ,20- dione in 10 ml. of benzene and 100 ml. of methanol. This solution was cooled rapidly in an ice bath and 2 ml. of 50% sodium hydroxide solution were added under stirring, followed by 5 ml. of hydrogen peroxide. The reaction was allowed to proceed for 18 hours at +5 C. and at the end of this time the excess hydrogen peroxide was destroyed with 0.2 g. of 5% palladium-on-calcium carbonate under stirring for 10 minutes. After removing the insoluble material by filtration, the filtrate was neutralized by the addition of 10% aqueous acetic acid. The solvent was then removed in vacuo and the crystalline material which formed was collected by filtration, washed with methanol and dried in vacuo, to give 0.37 g. of material melting at 207-2ll C. Crystallization from methanol and acetone-Skellysolve B hexanes gave pure 6a-methyl-9a-fluoro-115-hydroxy-16,17-oxido l,4-pregnadiene-3,20-dione of melting point 275-278 C. having. an analysis as follows:

Analysis.Calcd. for C I-1 0 1 C, 70.60; H, 7.22; F, 5.08. Found: C, 70.48; H, 7.27; F, 5.14.

A solution was preparedcontaining 1 g. of 6a-methyl- ..--fluoro-1lfl-hydroxy 16,17 oxido-1,4-pregnadiene-3, ZG-dione in 30: ml. of acetic acid. To this solution was added 1 ml. of 30.to 32% hydrogen bromide in acetic acid. After 4 hour at 25 C. and 3 hoursat +5 C., the reaction mixture was diluted to 250 ml..with ice water and filtered. Thefilter cake was washed. carefully with water and dried invacuo over anhydrous potassium. hy droxide at 25 C. to give. 096 g. ofthe. crude bromohydrin, 16)3*bI'OmO-6OCrmCthyl'9(XrflUOYO 115,170- dihydroxy!1,4-pregnadiene-3,20-dione melting at 1.47- 155' C. Recrystallizing this material from acetone- Skellysolve. B: hexanes. gave pure 16,8-br0n'iO-6u-nl6th3'l- 9a-fluoro-115,l7a-dihydroxy-1,4 Iegnadiene-lZO-dione of. melting. point 1'5'3,160 C. and having the following.

analysis:

Analysis.Calcd. forC H' BrFO C, 58.06; H, 6.20; F, 4.17; Found: C, 58.08;,H, 6.21,; F, 3.92;

A solution of 0.56 g. of 16,6-bromo6a-methyl-9o:- fluoro l'113,17a-dihydroxy-l,4-pregnadiener3,20-dione in 25 ml. of methanol was-refluxed'with 0.28 g. of. Raney nickel. for 2 hours, thenwas; cooled and filteredl The filtrate was evaporated to give 0.5 g. of a white foamy materialwhich was chromatographed on g. of Florisil, usinggradient.elutionwith 4 l. of acetonc-Skellysolve B hexanes fromO to. 40%. This gave only a partial separation.

rystallization of the least polar fractions from acetone-Skellysolve B hexanes gave 40 mg. of 6u-methyl-9w fluoro-l1;8 hydroXy-1'6,17 oxido-1,4 pregnadiene 3,20- dione. Slightly more. polar fractions were crystallized twice from acetone=Skellysolve Bhexanes to give 99 mg. of 16m-bromo-6a-methyl-9a-fluoro-1 1 5,17a dihydroxyl,4-pregnadiene-3,20-dione of. meltingpoint 262-272" C. with decomposition and having an, analysis as follows:

Analysis.Calcd. for C l-l Brlo z Br, 17.55; F, 4.17. Found: Br,'l7.43; F, 4.35.

Example 2.16a-Z1r0m0-11B,1 7ec,21'trihydr0xy-4-pregnene-3,20-di0ne, 21-acetate A mixture was prepared containing 16/8-bromo-17a, 2l-dihydroxy-4-pregnene-3,20-dione [obtained in, crude form by reacting 20 g. of l6a, 17 a-oxido-4-pregnen-2l-ol- 3,20-dione acetate with hydrogen bromide and-submitting the bromohydrin to acid solvolysis as described by W. T. Moreland, et al., J. Am. Chem. Soc. 84, 2966 (1962)]. in 78-0 ml. of methanol and containing 9.75 g. of Raney nickel priorly washed with acetic acid, and methanol. This mixture was refluxed under vigorous stirring for a period of 4 hours. The reaction mixture was then cooled, filtered through Celitediatomaceous earth and evaporated. The residue remaining from the evaporationwas recrystallized from aqueous methanol tojgive, 995 g. of 16oz-bromo-17u,21-dihydroxy-4-pregnene-3,ZO-dione of melting point 146-155 C. with decomposition.

This material was acetylated ina mixture consisting of acetic anhydride and pyridine at 25 C. After the reaction was terminated the mixture was poured into ice water andthe precipitate collected and recrystallized from acetone-Skellysolve B hexanes to give 8.65 g. of 16abromo-17a,21-dihydroxy-4-pregnene-3,ZO-dione 21-acetate of melting point 202 -203 C. and the following analysis.

Analysis.Ca1cd. for C H BrOg (467.42): C, 59.10; H, 6.69; Br, 17.10., Found: C, 59.02; H, 6.86; Br, 17.16.

Two grams of 16a-bromo-l7u,2l-dihydroxykpregnene-3,20-dione, 21-acetate was fermented with a 72 After'the fermentation was completed, the fermentation brothwas extracted several times with ethylene dichloride arid the ethylene dichloride washed with water and thereupon evaporated to give a solid material. This material 7 .was dissolved again in methylene chloride, the methylene chloride solution washed with water, dried over anhydrous sodium sulfate and evaporated to give 1.17 g. of a tan foam of crude lfia brom'o-l113,17a-,2l-trihydroxy-4- pregnene 3,20-'dione. A portion of 0.67 g. of this 16: bromo-11B,17a,21-trihydroxy-4-pregnene 3,20-dione was acetylated with acetic anhydride and pyridine at room temperature, the reaction mixture was poured into water and extracted with methylene chloride. The methylene chloride extracts were then combinedand evaporated to give 0.59 g. of crude 16a-bromo-115,17,2l-trihydroxy- 4 pregnene-3,20-dione 21-acetate which was] chromatographed over Florisil anhydrous magnesium' silicate. Fractions with 2 /2, 5, and 12/2% acetone-balance Skellysolve B hexanes were discarded and the fractions obtained with 15% acetone-85% Skellysolve B hexanes were combined, evaporated and the material recrystal-' lized from .acetone-Skellysolve B hexanes to give 0.22 g.'

of 16oz bromo-11B,17,2l-trihydroxy-4-pregnene-3,20 dione, ZI-acetate of melting point 193-197 C. This 21- acetate was recrystallized again from methanol to give pure 16m bromo-1lfi,17o6,2l-trihydroxy-4-pregnene-3,20- dione, 21-acetate of melting point 197-200 C. and having an analysis as follows:

'Analysis.Calcd. for C H BrO (483.42) C, 57.14;

H, 6.46; Br, 16.53. Found: C, 57.61; H, 7.06; Br, 15.90.

Example 3.16u-br0m011fl,17a,21-trihydrbxy-l,4-

pregnaaiene-3,20-dione, 21 -acetate 7 7 One and three-tenths grams of l6o bIOmO-17a,2l-d1- dium bicarbonate, was stirred for 10' minutes and then allowed to stand at room temperature for 2 hours. The

reaction mixture was thereupon poured into 100 ml. of

ice-water and the mixture put in the refrigerator overnight (about 16 hours at 5 C.). The mixture was then filtered and the precipitate washed with water. Thereafter, the precipitate was recrystallized twice from meth anol to give the free alcohol 16m-blOmOllB,l7a,2l-trihydroxy=1,4-pregnadiene-3,20-dione.

Example 5.-16a-br0mo-11B,l 7a,21 trihydr0xy-1,4

pregfiadiene-iZO-dione, 21 -benz0ate 'ice'waten. The ice water solution was transferred'to a refrigerator atS" C. and was allowed to stand'there for a period of 2 hours. Thereafter the solution was filtered and the precipitate collected on a filter, washed repeatedly with water. It wasthen recrystallized 3 times from aqueous methanol to give pure l6 -bromo-1 1/3,l7,21-trihydroxy-l,4-pregnadiene-3,20-dione 21-benzoate. V 7

Example 6.16x-br0m0-11,B,17oc,21 trihydr0xy-1,4-

The organic layer was separated, dried over magnesium sulfate and evaporated, leaving a yellow foam of 1.09

g. weight. This foam was acetylated in a solution of 2.6 ml. of acetic anhydride and 1.3 ml. ofpyridine at room temperature. poured into water and the material filtered, 1 giving 1.1 g. of a white foam. This foam was chromatographed over 100 g. of Florisil anhydrous magnesium silicate The reaction mixture was thereupon:

showing a peak in the fractions consisting of 15% ace- Y Recrystallizagave pure l6 -bro'mo-l13,17u,2l-trihydroxy-lA pregna- 'diene-3,20-dione, 21-acetate'of melting point 22523l C. i

and having the following analysis; V

' Analysis.'Calcd.for C H BrO (481.38): C, 57.38;

H, 6.07; Br, 16.60. Found: C, 57.42; H, 6.00; Br, 16.20. The nuclear magnetic resonance showed that this was indeed a A steroid. I

. Example 4.16 cxbr0mo-11 3,17a,21-trihydroxy-l,4- pregnadiene-3,20-di0rze V one gram of 16a-bromo-11,6,17d,21 trihydroxy-1,4-

pregnadiene-3,20-dione, ZI-acetate, dissolved in 20 ml. of

. methanol containing 0.5 ml. of water and 0.5 g. of so-.

' pregnadiene-i ZO-dione, Z-(fi-cyclopentylpro pianate) In the same manner given in Example 5, 0.5g. of16a' bromo 11,3,17a,21-trihydroxy-1,4-pregnadiene-3,20=dione in pyridine solution was reacted with 2 ml. of ,B-cyclopentylpropionyl bromide. After recrystallizationffrom methanol 16oz bromo-11,8,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione,' 2l-(B-cyclopentylpropionate) =was ob (d) With lauryl chloride gave' 16otbr0m0ll,8,17a,21-

trihydroxy-l,4-pregnadiene-3,20-dione, 21-laurate.

Example 7.16oc-br0m0-116,17a,21-trihydroxy-4- V 7 pregnene3,20-dione In the manner given in Example 4, ISa-bromo-llfi, l7a,21-trihydroxy-4-pregnene-3,20-dione, 2l-acetate was hydrolyzed inmethanolin the presence of sodium bicarbonate to give the free. alcohol 16a-brorno llfi,17c,2'I

trihYdroxy-4-pregene-3,20 dione.

Example 8.16a-brom0-11,8,] 7a,2l-trihydroxy'4-f pregnene-3,20-dione, ZI-propionate In the manner given in Example 5, 16a-bromo-'11B,17a, 21-trihydroxy-4-pregnene-3,20-dione, dissolved in pylfidine, was reacted with propion-ic acid anhydride to give 1600' bromoallfl,17a,21-trihydroxy-4-pregnene-3,20-dione, propionate.

Example 9.16a bromo I1f-3,17a,2] triliydmxy 4- V pregnene-3,20-di0ne, v 21 -phenylacetate In the manner given in Example 6, l6a-brorno-llfid7u,

21-trihydroxy-4-pregnene-3,20 dione, dissolved in pyridine, was reacted with phenylacetyl chloride to give l6o-bromo 1 1fi,17a,2 1-trihydroxy-4-pregnene-3,20-dione, 2l-phenyl acetate. w r f In the same manner as given in Examples 5 and 6 other esters of 16aa-b1'OII10-ll 1S,17a,21-trihydoxyr4-pregnene- 3,20-dione can be prepared by reacting thisfste roid in pyridine solution with anhydrides and acyl halides of selected.

organic carboxylic acids, Representative other esters thus prepared include the butyrate, valerate, hexanoate, hept-anoate, octanoate, decanoate, laurate, phenylpropionate, isobutyrate, B-cyclopentylpropionate, and the like of 16abromo- 1 1 3,17cc,2 1-trihydroxy-4-pregnene-3,ZO-dione.

Example 10.16-iodo-J7c,21-dihydr0xy-4-pregnene- 3,20-dz'0ne, 21 -acetatc A solution of 2l-hydroxy-l6d,l7ot-oxido-4 pregnene- 3,20-dione acetate in acetic acid was reacted with hydrogen iodide and. submitted to acid solvolysis to give l6 3-iodo- 170:,2l-dihydroXy-4-pregnene-3,20-dione. The crude material obtained in this reaction was stirred and refluxed in methanol with Raney nickel for 4 hours to give 16a-iodo- 17rx,21-dihydroxy-4-pregnene-3,ZO-dicne. The mixture was then cooled and filtered and the filtrate evaporated. The thus-obtained material was once recrystallized from methanol and was used in this form for acetylation in an acetic anhydride-pyridine mixture. After recrystallization of the material obtained from this esterification procedure, pure lcz-iodo-l7u,2l-dihydroxy-4-pregnene-3,20- dione, Zl-acetate was obtained.

Example 11 .16 1-i0d0-1 1B,] 7a,21-trihydr0xy-4- pregnene-3,20-dine 21 -acezate Two grams of l6 x-iodo-17u,2l-dihydroxyi-pregnene- 3,20-dione ZI-acetate were submitted to fermentation with Cunninghamella blalcesleeana under the conditions described in US. Patent 2,735,800. After the fermentation was completed the material obtained was extracted with ethyleen dicldoride, the ethylene dichloride fractions were washed with Water, combined, dried over anhydrous sodium sulfate, and evaporated. The crude material thus obtained was immediately =acetyla-ted in acetic anhydridepyridine at room temperature. The mixture, after standing at room temperature for 2 hours, was poured into ice Water, transferred into a refrigerator at 3 C. for 1 hour, thereupon filtered and the thus-obtained precipitate washed with water and recrystallized 2 times from acetone-Skellysoive B to give l6a-iodo-llB,l7a,21 trihydroxy-4-preg nene-3,20-dione, Zl-acetate.

One gram of 16a-iodo-l1,8,l7a,2ltrihydroxy-4-pregnone-3,20-dione, 21-acetate was refluxed with 0.5 g. of

I selenium dioxide in 50 ml. or" t-butyl alcohol for a period of 24 hours. The mixture was then filtered and the filtrate was evaporated. The dry material was dissolved in ml. of methanol and the solution thus obtained was filtered again. The thus-obtained fitrate' :was concentrated until crystallization began, hence it was allowed to cool to room temperature and finally in a refrigerator to 5 C. The thus-obtained crystals were recovered by filtration, dried in vacuo and twice recrystallized from aqueous methanol to give pure 16a-iodo-llfi,l7a,21-trihydroxyl,4-pregnadiene-3,20-dione, ZI-acetate.

In the same manner given in Example 4, 16u-iodo- 11,8,l7u,21-trihydroxy-4-pregnene-3,ZO-dione, ZI-acetate and la-iodo-l l S, l7a,21-trihydroXy-l,4-pregnadiene-3,20- dione, 21,-acetate can be hydrolyzed in methanol with sodium or potassium bicarbonate, sodium carbonate, or potassium carbonate to give the corresponding free. alcohols, 16oz iodo-llc,l7a,2l-t1ihydroxy-4 pregnene-3,20- dione and 16a-iodo-115,-17m,2Ltrihydroxy-lA-pregnadiene-3,20-dione.

The free alcohols, 1GCL-iOdO-1{1fi,17l1,21-tfilhYdTQXY-4- pregnene-3,20-dione and lfia-iodo-ll5,17a,2l-trihydroxy- 1,4-pregnadiene-3,20-dione, can he esterified in conventional manner as shown in Examples 5 and 6 to give the corresponding 21-esters. Representative esters thus obtained include the 2l-propionate, -.butyrate, -valerate, -heptanoate, -cctanoate, -laurate, phenylacetate, -phenylpropionate, -ethylbenzoate, -isobutyrate, -isovalerate,

- 6 9-cyclopentylpropionate, -hexanoate, -decanoate, and the like of 1ficc-iodo-l1,5,1 7a,2l-trihydroxy-4-pregnene-3 ,20- dione and sl6a-iodo-lllfi,lf7a,2l-trihydroxy-1,4pregnzadiene-3,20-dione.

Example 13.-16a-br0m0-9a-flu0r0-1 1 3,1 70:,21 trihydr0xy-4-pregnene-3,20-dione, 21 acetate To-a solution of 0.55 g. of 16oc-l31'OmO-1lfi,17u,21-flihydroxy-4-pregnene-3,ZO-dione, 2l-acetate in l2 ml. of pyridine was added 0.3 g. of N-bromoacetamide. After standing at room temperature for a period of 15 minutes the reaction mixture was cooled to 5 C. and with shak ing sulfur dioxide was passed over the surface until the solution gave no color with acidified starch iodine paper. The temperature was maintained in the range of 10 to 20 C. After termination of the reaction, the mixture was poured into 200ml. of ice water and the resulting precipitate collected by filtration. This material consisted of 16a bromo 17a,2l-dihydroxy-4,9(1l)-pregnadiene- 3,20-dione, 2l-ac-etate and was immediately used for the next step.

The 1 Soc-bI'OInO-1711,21-dihYdIOXY-4fi 1 1 -pregnadiene- 3,20-dione, ZI-acetate, as obtained above, was dissolved in a mixture of 3.5 ml. of methylene chloride and 6.2 ml. of t-butyl alcohol. A. solution of 0.55 ml. of 70% perchloric acid in. 0.43 ml. of water was added followed by a solution of 0.086 g., of; N-bromoacetamide in 0.86 ml. of t-butyl alcohol. Theresultant solution was stirred at 25 C. for 15 minutes, then a solution of 0.086 g. of sodium sul-fite in 0.86 ml. of water "was added and solvents were evaporated at reduced pressure. The. residue was partitioned between methylene chloride-water; the methylene chloride extract was. dried and evaporated to give 0.216. g; of 9a, 16a-dibrorno-l1,8,17:2,2'1-trihydroxy-4-pregnene-3,20-dione, Zl-acetate, which was used directly in the next step.

To a solution of the above-obtained 9a,16u-dibromo- 11B,17u,21-trihydroxy-4-pregnene-3,ZO-dione, Zl-acetate in acetone (6 ml.) was added 0.24 g. of potassium acetate and the resulting suspension stirred. under reflux for 16 hours. The mixture was evaporated to dryness leaving a. residue. Thisresidue was partitioned between methylene chloride and water. The methylene chloride extract was dried, evaporated and the residue chromatographed on 25 g. of. Florisil anhydrous magnesium silicate. The principal fractions eluted with 15% acetone- Skellysolve B hexanes consisted of 0.12 g. of l6a-bromo- 95,115 oxido 17a,21-dihydroxy-4-pregnene-3,20-dione, 21-acetate.

The thus-obtained 16a-bromo-9B,llfi-oxido-17a,21-dihydroxy-4-pregnene-3,ZO-dione, 21-acetate dissolved in methylene chloride (2 ml.) was cooled to 70 C. and added to a mixture of 2.0 g. of hydrogen fluoride and 3.5 ml. of tertahydrofuran at -20 C. The mixture was allowed to stand 16 hours at 20 C. and'4 hours at +5 C. At the end of this period it was mixed cautiously with an excess of cold sodium bicarbonate solution and the organic material was extracted with ethyl acetate. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed over 10 g. of Florisil anhydrous magnesium silicate using Skellysolve B hexanes-acetate mixture as eluents. The portion containing a peak fraction was evaporated and the product recrystallized from ethanol giving 34 mg. of l6a-bromo-9a-iluoro- 11 3,l7m,2l-trihydroxy-4-pregnene-3,20-dione, 2l-acetate of melting point 220-227 C. and having an analysis as follows:

Analysis.Calcd. for C H FBrO (501.39): F. 3.79. Found: F. 3.22. V

In the same manner as given above 16a-bromo-11 3, l7a,2l-trihydroxy-1,4-pregnadiene-3,20-dione, 2l-acetate was converted to 16a-bromo-9a-fluoro-1lfi,17u,21-trihydroxy-1,4-pregnadiene-3,ZO-dione, 21-acetate.

In the same manner given in Example 13, 16a-iodo- 7-. 11B,17u,21 trihydroxy 1,4 pregnadiene-3,20-dione, 21-

trihydroxy-1,4-pregnadiene-3,20-dione, 21-acetate.

In the manner given in Example 4, l6a-bromo-9afiuoro-l1fi,17 x,2l-trihydroxy-4-pregnene-3,ZO-dione, 21- acetate was hydrolyzed in a solution of methanol in the presence of potassium bicarbonate to give the free alcohol, l6 u-bromo-9u-fluoro-l1B,l7bt,21-trihydroxy-4-preg' nene-3,20-dione.

In the same manner as above l6a-bromo-9a-fluoro- 1113,17cc,21 trihydroxy 1,4 pregnadiene-3,20-dione, 21-- acetate was converted to the free alcohol, 16oc-br0m0-9rxfluoro-l l5, 170;,2 l-trihydroxy-l,4-pregnadiene-3 ,ZO-dione.

, In the same manner as above l6u-iodo-9q-fluoro-llp, 17a,2l-trihydroxy-1,4-pregnadiene-3,ZO-dione, 21-acetate was converted to the free alcohol, 16u-i0d0-9ot-flll0l0- 1 1,8, 17a,21-trihydroxy-1,4 pregnadiene-3 ,20-dione.

In a manner analogous to Example 5, 16a-bromo-9u 11B, 171:,2 1 tiihydroxy-4-pregnene-3,ZO-dione, 21- butyrate;

(b) Valerie anhydride to give 16oc-b1'OI110-90t-fl11010- 1 1p, 17:1,21-trihydroxy-4-pregnene-3,ZO-dione, 21-valerate; (c) Phenylpropionic anhydride togive'16oc-bromo-9u 'fluoro-l1 3,17 21-trihydroxy-4-pregnene-3,ZO-dione, 21-

phenylpropionate;

' (d) Lauryl chloride to give 16u-bromo-9a-fluoro-l1fl, l70:,21-trihydroxy4-pregnene-3,2O-dione,i 2'1-laurate;

(e) fl-cyclopentylpropionyl chloride to give 16:.

dione, 21-(fl-cyclopentylpropionate); Example 17 v In the manner as given in Example 5, a pyridine solution of. 16a-bromo-9a-fiuoro-11fi,17a,21-trihydroxy-1,4-'

pregnadiene-3,20-dione is reacted with:

(a) Butyric anhydride to give 16ez-brorno-9oc-fluoro- 11fl,l7a,21-trihydroxy-1,4-pregnadiene-3,20-dione, 21-butyrate;

(b) Valeric anhydride to give '16u-bromo-9ot-fluoro- 1lfi,17u,21 trihydroxy 1,4-pregnadiene-3,20-dione, 21- valerate; v

(c) Phenylpropionic anhydride to give 16oc-b1Om0-9ucfiuoro l1,3,17a,21-trihydroxy-1,4-pregnadiene-3,ZO-dione,

ZI-Phenylpropionate; I (d) Lauryl chloride to give 16cc-bI'OmO-9pc-fiu01O-1lfi, 170:,21 trihydroxy l,4-pregnadiene-3,20-dione,,21-laurate;

(e) B-cyclopentylpropionyl "chloride to 'give 16ozbI'OmO-9oc fluoro-l 1B, 17,211trihydroxy-1,4-pregnadiene- 3,2O-dine, 2l-(B-cyclopentylpropionate).

Likewi se as described in Example 13, l6 z-iodo-llfi,

176:,21-trihydroxy-4-pregnene-3,ZO-dione, ZI-acetate is treated with N-brornosuccinimide in pyridine and then .(11)-pregnadiene-3,20 dione, 2l-acetate.

7 with sulfur dioxide to give 16m-iodo-l7at,2l dihydroxy-4,9

- boxylic acids containing from. 1 to 12'carbon atoms.

V r 'In the manner given inExample '1, 6a-methyl-9a The thus-obtained 4,9(11)-pregnadiene is treated in t-butyl alcohol with N-bromoacetamide and aqueous perchloric acid to give 9ot-bromo-l6ix-iodo-l1,B-17:i,21-trihydroxy-4-pregnene-3,ZO-diohe, 2l-acetate.

911- bromo 16a iodo-.11,8,17a,21-trihydroxy-4-pregnene-3,20-dione, 2l-acetate, as obtained above, is treated with potassium acetate inacetone solution to give 160:- iodo 95,11 3 oxido-17a,21-dihydroxy-4 pregnene-3,2'0- dione, 21-acetate which was reacted with hydrogen fluopregnene-3,20-dione, 21-acetate.

Example 19.16a-i0d0-9ct-flw0ro-11,3,17a,21-trihydroxy-4-pregnene-3,ZO-dione i Likewise as described in Example 4, 16oc-iOd0-9opfiuoro l15,l7a,2l trihydroxy-4-pregnene-3,20 dione, 21- acetate 'is hydrolyzed in methanol solution with potassium bicarbonate. The product after recrystallization was pure 16u -iOd0 9m-fluoro-11,8,17u,21-tril1ydroxy-4-pregnene-3,20-dione.

Likewise as shown iodo 90c fluoro-l1p,17a,2l-trihydroxy-4-pregnene-3,20-

dione can be obtained by reacting this steroid in pyridine solution with selected acyl halides and acid anhydrides of organic carboxylic acids, especially hydrocarbon 'car- Representative esters thus prepared include the 21 -propionate, -butyrate, -valerate, -hexanoate,'-heptanoate, -octanoate, -decanoate, -laurate, -fi c'yclopentyl-propionate,'

-isobutyrate,' -benzoate, -ethylbenzoate, -phenylacetate,

phenylpropionate, and the like of 16a-iOdO-9a-flup1'Q-1lfi, V

17,21-trihydroxy-4-pregnene 3 ,20-dione.

6oa-methyl-1 ,4-pregnzzdz'ene-3,20-q'ione.

fiuoro 11B hydroxy-16,l7-oxido-1,4-pregnadiene-3,20- dione inacetic acid was reacted with hydrogen iodide. After 4 hour at room temperature and 3 hours in a refrigerator at 5 C., the reaction mixture was diluted with ice water and filtered. The filter cake was carefully washed with water and dried in vacuo over potassium Magerlein et al.:- Chemistry and Industry}? No. 50, a

hydroxide to give l6fi-iodo-9a-fiuoro-l113,17a-dihydroxy- 6a-methyl-l,4-pregnadiene-3,ZO-dione.

This 16,8-iodo steroid Was refluxed in methanol so1u-' tion in the presence of Raney nickel for. 2 hours. The

reaction mixture was cooled and filtered; The filtrate was evaporated to give a whitish foam material which was chromatographed. over Florisil with gradient elution consisting of acetone and Skellysolve B hexane mixtures;

The peak fraction was isolated and recrystallized to give a pure 16a-i0d0-90z-fl11010-1 1,8, 17a-dihydroxy-6a-methyl-l,

4-pregnadiene-3,20-dione.

, Iclaim:

nene-3,20-dione, 21-acetate. V v

2. 16oz iodo l1/3,17 11,21 trihydroxy-4-pregnene-3,20- dione, 21-acetate.

References Cited by the Examiner UNITED STATES PATENTS 1/ 62 Magerlein et al. 260'39,7 .45

I 3,022,295 2/62 .Berg'ct a1. 260239.55 3,049,556 8/62 Hirschmann 260-397.45 7

3,062,846 11/62 Fried 2 60 -3 914 3,137,712 6/64 Birkenmeyer et al. 260,397.4S

OTHER REFERENCES D ec. l6, 1961, pp. 2050-2051. I V LEWIS GOTTS, Primary Examiner. I

hereinabove, other esters of 16x-' 

1. 16A-BROMO-9A-FLUORO-11B,17A,21-TRIHYDROXY-4-PREGNENE-3,20-DIONE,21-ACETATE. 